Cadherins are cell-cell adhesion glycoproteins that form calcium-dependent inter-cellular junctions and play an essential role in morphogenesis and in the development and maintenance of adult tissues and organs (NPL 1). During embryogenesis, the cell expression of specific cadherins results in homophilic interactions that are critical in the process of cell sorting and tissue stratification (NPL 2-4). Alterations in these cellular attachments play an important role in cell destabilization and may modify the carefully regulated differentiation process of the epithelial structures (NPL 5-6). For this reason, the functional loss or overexpression of cadherins and the molecular mechanisms underlying the control of the genes codifying these proteins have been implicated in carcinogenesis (NPL 7).
The cadherin family is subdivided into various subfamilies, including the classical E-, P-, and N-cadherins, each demonstrating a specific tissue distribution (NPL 8). Although E-cadherin is expressed in all epithelial tissues, the expression of P-cadherin (CDH3) is only restricted to the basal or lower layers of stratified epithelia, including prostate and skin, and also to the breast myoepithelial cells (NPL 9-10).
A large body of evidence now also reveals that aberrant P-cadherin expression is associated with cell proliferation and with tumors of the colon, breast, lung, thyroid, and cervix (NPL 11-12). Human P-cadherin was reported to be the antigen recognized by the NCC-CAD-299 monoclonal antibody raised against a vulvar epidermoid carcinoma (NPL 10). Modulation of P-cadherin mediated adhesion and intracellular signaling is expected to result in decreased proliferation and survival of tumor cells in vivo. Accordingly, in view of the pivotal role that P-cadherin appears to possess in cell proliferation and solid tumor progression, it is desirable to generate antibodies to P-cadherin that can provide a therapeutic benefit to patients with a variety of cancers.
Monoclonal antibodies against cancer-specific molecules have been proved to be useful in cancer treatment (NPL 13). In addition to successful examples of clinical application of the humanized or chimeric antibodies such as trastuzumab (NPL 14), rituximab (NPL 15) and bevacizumab (NPL 16) for breast cancer, malignant lymphoma and colon cancer, a number of monoclonal antibodies against other molecular targets are in development and being evaluated their anti-tumor activities. These monoclonal antibodies are expected to provide a hope to patients having tumors that have no effective treatment. One of the other important issues for these monoclonal antibodies is achievement of selective therapeutic effects to cancer cells without severe toxicity due to their specific reaction to cells expressing target molecules (NPL 17-19, PTL 1-4).